Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite a relatively low prevalence, it accounts for a disproportionate number of deaths, due to its resistance to any therapeutic approach. The vast majority of ATCs is associated with oncogenic mutations of BRAF or alterations of members of the PISK signaling pathway, and has a very high frequency of TP53 mutations. Based on these genetic data, our group and Dr. Fagin's group have developed two clinically relevant mouse models of ATC by combining thyroid-targeted Tp53 loss with homozygous deletion of Pten or expression of oncogenic Braf. These mice develop with very high penetrance ATCs that display all the features of their human counterpart, including high mitotic index, pleomorphism, epithelial-mesenchymal transition, aneupioidy, local invasion, and distant metastases. The analysis of these novel models has revealed that i) several groups of genes encoding components of major signaling pathways, including mitotic kinases, are markedly overexpressed in mouse ATCs independent of their driver oncogenic alteration, and ii) despite their genetic instability, these tumors are still remarkably sensitive to the inhibition of their oncogenic driver pathway. We propose to extend these studies 1) to validate our findings in a large set of genetically annotated human anaplastic thyroid tumors, 2) to establish whether mouse and human ATCs are sensitive to mitotic kinases inhibition, and 3) to assess the ability of pharmacologic inhibitors ofthe driver oncogenic pathways to increase the efficacy of cytotoxic chemotherapy by blocking critical signaling pathways that contribute to ATC resistance to these drugs. These studies will lay the foundation for new clinical trials for ATC to be carried out during the next project period.